There is a high comorbidity between nicotine dependence and major depressive disorder (MDD). Smokers with comorbid MDD are more likely to become dependent on nicotine, more severely dependent, and experience more serious withdrawal symptoms than smokers without MDD. MDD also has a negative impact on the outcome of smoking cessation treatments. The neurobiological mechanisms of nicotine dependence and comorbid MDD are unknown. We propose to assess the activity of the brain reward system (BRS) as a possible neurobiological link between MDD and nicotine dependence. Although many neurotransmitters are involved in the pathophysiology of these two disorders, we propose that: 1) A dysfunctional dopaminergic BRS may be responsible for some mechanisms involved in nicotine dependence and MDD; and 2) Smoking may modulate the activity of the BRS by enhancing dopaminergic activity relieving some depressive symptoms (e.g., anxiety). We propose two human experimental studies. Study I will a) assess the activity of the BRS by measuring the effects of a single oraF dose of d-amphetamine (d-amph) in depressed (DSM IV diagnosed, not on antidepressants, n=20) and non-depressed smokers (n=20); b) determine whether nicotine modifies the response to d-amph; and c) determine whether nicotine withdrawal symptoms are different during smoking and non-smoking conditions. We will measure physiological and rewarding effects of d-amph using valid self-report instruments at baseline and 30, 60, 120, 180, and 240 min post-drug. Plasma levels of damph and homovanillic acid will be measured. Study 2 will use PET to measure dopamine-medialed ['C] Raclopride displacement before and after 30mg of d-amph in 24 control and 24 MDD (12 smokers and 12 non-smokers/group) subjects. It will also determine whether the rewarding effects of d-amph correlate with ['C] Raclopride displacement. Results may provide evidence for neurobiological mechanism (s) explaining the high comorbidity between MDD and nicotine dependence. The BRS could become the target for developing new treatments for nicotine dependence and some symptoms of MDD.